Clinic for Horses, University of Veterinary Medicine Hannover, Bischofsholer Damm 15, 30173 Hannover, Germany.
Naunyn Schmiedebergs Arch Pharmacol. 2010 Feb;381(2):161-9. doi: 10.1007/s00210-009-0481-1. Epub 2009 Dec 15.
Macrolide antibiotics penetrate in the lung against steep concentration gradients into the epithelial lining fluid (ELF) and broncho-alveolar cells (BAC). Since they interact with ABCB1, ABCC2, and organic anion transporting proteins (OATPs), which are localized to lung tissue, pulmonary concentration may be influenced by rifampicin (RIF), an inducer and modulator of efflux and uptake transporters. We measured concentrations of tulathromycin (TM) in plasma, ELF and BAC in 21 warm-blooded foals 24 and 192 h after first and last intramuscular injection of 2.5 mg/kg TM once weekly for 6 weeks. In 11 foals, TM was combined with RIF (10 mg/kg twice daily), and mRNA expression of ABCB1 and ABCC2 in BAC was assessed before and after RIF. Affinity of TM to ABCB1 and ABCC2 was measured by transport assays using cell monolayers and membrane vesicles of MDCKII and 2008 cells transfected with ABCB1 and ABCC2, respectively. At steady state, TM concentrated manifold in ELF and BAC. Comedication of RIF significantly decreased the AUC of TM (18.5 +/- 4.0 versus 24.4 +/- 3.7 microg x h/ml, p < 0.05) and lowered its concentrations in plasma (24 h, 0.17 +/- 0.05 versus 0.24 +/- 0.05 microg/ml; 192 h, 0.05 +/- 0.01 versus 0.06 +/- 0.01 microg/ml) and BAC (24 h, 0.84 +/- 0.36 versus 1.56 +/- 1.02 microg/ml; 192 h, 0.60 +/- 0.23 versus 1.23 +/- 0.90 microg/ml, all p < 0.05). Treatment with rifampicin did not markedly induce ABCB1 and ABCC2 expression. TM had no affinity to ABCB1 and ABCC2 in vitro. Concentration of TM in the lung of foals was significantly lowered by comedication of rifampicin most likely caused by extrapulmonary mechanisms leading to lower plasma concentrations.
大环内酯类抗生素能够在肺部通过陡峭的浓度梯度穿透上皮衬液（ELF）和肺泡细胞（BAC）。由于它们与 ABCB1、ABCC2 和有机阴离子转运蛋白（OATPs）相互作用，而这些蛋白都定位于肺部组织中，因此肺部的浓度可能会受到利福平（RIF）的影响，RIF 是外排和摄取转运蛋白的诱导剂和调节剂。我们测量了 21 匹温血驹在第 1 次和第 6 次每周 1 次肌内注射 2.5mg/kg 妥他霉素（TM）24 和 192 小时后的血浆、ELF 和 BAC 中的 TM 浓度。在 11 匹驹中，TM 与 RIF（10mg/kg 每日 2 次）联合使用，并在使用 MDCKII 细胞单层和膜囊泡以及分别转染了 ABCB1 和 ABCC2 的 2008 细胞的转运测定中评估了 RIF 前后 BAC 中 ABCB1 和 ABCC2 的 mRNA 表达。通过使用 MDCKII 细胞单层和膜囊泡以及分别转染了 ABCB1 和 ABCC2 的 2008 细胞的转运测定，测量了 TM 与 ABCB1 和 ABCC2 的亲和力。在稳态时，TM 在 ELF 和 BAC 中大量浓缩。利福平联合用药显著降低了 TM 的 AUC（18.5±4.0 与 24.4±3.7μg x h/ml，p<0.05），并降低了其在血浆（24 小时：0.17±0.05 与 0.24±0.05μg/ml；192 小时：0.05±0.01 与 0.06±0.01μg/ml）和 BAC（24 小时：0.84±0.36 与 1.56±1.02μg/ml；192 小时：0.60±0.23 与 1.23±0.90μg/ml，均 p<0.05）中的浓度。利福平治疗并未明显诱导 ABCB1 和 ABCC2 的表达。TM 在体外与 ABCB1 和 ABCC2 没有亲和力。利福平联合用药后，驹肺部的 TM 浓度明显降低，很可能是由于肺外机制导致血浆浓度降低所致。
